Opioid agonist analgesic drugs are generally administered to reduce or relieve pain. Examples of such drugs are morphine, meperidine, fentanyl, opium and hydrocodone. There are many other opioid agonist analgesic drugs to which the present invention applies.
Unfortunately, administration of an opioid agonist analgesic drug over a prolonged period of time, as common for treating many pain syndromes, generally results in the development of physiological tolerance to said opioid agonist analgesic drug, whereby an increasing amount of said opioid agonist analgesic drug is required over time to produce an equivalent analgesic effect. This may lead to chemical dependence upon the opioid agonist analgesic, whereby abrupt withdrawal of opioid agonist drug will produce physical signs and psychological symptoms that, in general, are opposite to those positive effects which the opioid agonist originally produced. Such withdrawal signs include excitation of the sympathetic nervous system such as release of norepinephrine from the locus coeruleus in the brain, increased heart rate and blood pressure, increased respiratory rate, altered gastrointestinal function leading to nausea, vomiting and/or diarrhea, piloerection ("goose bumps"), pain, and psychological or psychosomatic symptoms such as experiencing "hot and cold flashes," difficulty sleeping and chills. Abdominal cramps, aches and pains--especially cramping in the legs, and involuntary movement--especially kicking of the legs, and feeling weak are other complaints associated with withdrawal of opioid agonists from a human chemically dependent upon them. In general, this myriad of signs and symptoms is what is known colloquially as being "dope sick." It is this dope sickness that often is the incentive for humans chemically dependent upon opioid agonists to seek out and self-administer opioid agonist analgesic drugs without proper supervision by a medical professional. When other behavioral factors come into play, such as impairment of social functioning, criminal behavior to support use of the opioid agonist drug, and/or psychiatric or psychological deterioration directly attributable to the drug's use, the human is said to have an addiction to the opioid agonist analgesic. Common opioid agonist analgesics to which humans are often addicted include heroin, methadone and their derivatives. Humans have the potential to become addicted to many other opioid agonist analgesic drugs.
There has been a long-felt need to develop ways of delivering opioid agonist analgesic drugs without causing, or attenuating to the greatest degree possible, negative effects of said drugs at their therapeutically prescribed doses. This is accomplished by striking the optimal balance of effects between dopamine-increasing opioid receptors, such as mu-opioid receptors, and dopamine-decreasing opioid receptors, such as kappa-opioid receptors. The present invention fulfills this need in a unique and novel way that has not been appreciated by those skilled in the all of opioid analgesics.
The present author describes in the application for U.S. Pat. No. 5,783,583 in great detail the unique characteristics common only to the opioid antagonist nalmefene which set nalmefene apart from other opioid antagonists such as, for example, naloxone and naltiexone. U.S. Pat. No. 5,783,583 ('583) further describes how the unique opioid receptor subtype binding profile of nalmefene enables nalmefene alone, as compared to naloxone and naltrexone, to allow preferred antagonism of opioids at the kappa-opioid receptors versus the mu-opioid receptors, which in turn, results in an optimal homeostatic balance of dopamine.
Szekely (Exhibit A) shows a schematic representation of two opposing opioid systems located in the mesolimbic system of the human central nervous system. These systems modulate A10 dopaminergic neurons projecting in the nucleus accumbens. As illustrated in Exhibit A, stimulation of mu-opioid receptors (the mu subtype of opioid receptor) in the ventral tegmental area (VTA), the site of origin of the A10 neurons, increase dopamine release in the nucleus accumbens (NA). Selective blockade of this mu-receptor results in significant decrease in dopamine release in the nucleus accumbens. In stark contrast, stimulation of kappa-receptors (the kappa subtype of opioid receptor) in either the VTA or the NA results in a decrease in the amount of dopamine released. Selective blockade of kappa-receptors significantly increases dopamine release.
Spanagel et al. (exhibit B) demonstrate that tonically active and functionally opposing mu and kappa opioid systems regulate mesolimbic dopamine release in the nucleus accumbens. They report that the injection of mu-opioid agonists such as DAGO into the VTA stimulate mu-opioid receptors and increase the release of dopamine from the VTA into the NA. As would be expected, administration of a mu-opioid receptor antagonist into the VTA decreases dopamine release. The authors further report that kappa-opioid receptors agonists such as U-6953 infused into the NA inhibit dopamine release there, whereas kappa-opioid receptor antagonists such as nor-BNI increase dopamine release. An "agonist" is a "like" chemical with similar action to a given drug. An "antagonist" is a chemical, often with a similar chemical structure to a given drug, which exerts a dissimilar action to the given drug, in general preventing the "like" action of that given drug. With opioid receptors, in general, an agonist binds to the receptor and activates it in such a way as to begin a cascade of chemical or pharmacological events so as to result in the end effect related to a particular opioid receptor subtype. In contradistinction, an antagonist will bind to the receptor but not activate it. An antagonist exerts its actions by blocking the receptors from agonists, by physically occupying the space on the receptor where an agonist would otherwise bind.
The opposing mu and kappa opioid systems acting together provide a homeostasis of dopamine levels within the central nervous system. Changes in these opioid systems, such as by activation or blockade of the specific receptors, would therefore be expected to modulate opioid-induced effects that are mediated by mesolimbic pathways. Mu and kappa receptors are found elsewhere in the human body. For example, they have been located in the spinal cord (See Fujimoto, Bakshi and Behrmann, below) and in other non-central nervous system organs such as the kidney and intestine (See Ohnishi and Kreek, below). Accordingly, the model presented provides a neurochemical framework for understanding the adaptive changes resulting from long term use of opioids, as well as the clinical response elicited by exogenously administered opioid agonists and antagonists having different binding profiles.
For example, modifications in opioid-induced behavior resulting from changes in these mu and kappa systems are reported by Pan et al (Exhibit C). These authors state that the effects of opposing mu and kappa receptors extend to opioid action on emotion, perception and drug reinforcement. While morphine and other mu-opioid agonists increase dopamine release and produce euphoria and place preference, kappa-opioid agonists reduce mesolimbic dopamine release and produce dysplioria and aversion.
Scientists have shown that nalmefene, relative to other opioid antagonists such as naloxone and naltrexone, is significantly more kappa-receptor preferring. By way of example, Kreek et al. (Exhibit D) conclude that nalmefene has more kappa binding activity than either naloxone or naltrexone. Specifically, nalmefene is more potent than either naloxone or naltrexone as a kappa-receptor antagonist, and therefore would block kappa agonists (e.g. the naturally occurring dynorphin) to a greater extent than the other antagonists.
Fujimoto et al. (Exhibit E) demonstrate differences between mu and kappa receptor effects in the spinal cord. Specifically, these authors report that the administration of dynorphin, a potent kappa agonist, results in decreased analgesia. The dynorphin causes antianalgesic effects at the level of the spinal cord. Fujimoto shows that when a kappa-opioid receptor antagonist such as Cholera Toxin is given, the antianalgesic effect of dynorphin is inhibited.
Bakshi et al. (Exhibit F) shows that kappa receptors are widely distributed in the spinal cord, and that administration of dynorphin causes motor impairment. These authors also demonstrate that nalmefene is selective for these intraspinal kappa receptors, and limits dynorphin induced motor dysfunction after spinal cord injury.
Behrmann et al. (Exhibit G) report that a single dose of nalmefene has increased activity at kappa receptors and that a single dose of nalmefene exerts a significant neuroprotective effect after acute spinal cord injury, in direct contrast to the mu-preferring opioid antagonist naloxone that showed no significant effect on neurological recovery after spinal cord injury.
Ohnishi et al. (exhibit H) teach the effects on urine production due to kappa-opioid receptor pharmacology at both the level of the pituitary gland and the kidney.
'876 makes no mention of the positive and negative effects of opioid agonists taught in the present invention. For instance, no mention is made in '876 regarding euphoria versus dysphoria, or behavioral effects such as emotion, perception, drug reinforcement and place preference. Further, '876 does not address effects upon intestinal function or urination. Perhaps most convincingly, however, is that '876 makes no reference to the opposing mu and kappa opioid receptors in maintaining a homeostatic balance of dopamine in the mesolimbic region of the brain, in the spinal cord, or at other peripheral sites such as the intestine or kidney.
Other investigators have contemplated preparations of opioid agonists in combination with naloxone. However, as '583 clearly shows, nalmefene and naloxone are not analogous compounds. Therefore, the present invention would not be obvious to one skilled in the art simply because naloxone has previously been combined with opioid agonists. In fact, because of naloxone's opioid receptor subtype binding profile, it could not exert the positive opioid effects as nalmefene at similar doses, as taught in the present invention.